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ThermoTRP channels are expressed in sensory neurons where they detect a variety of physical and chemical stimuli including temperature, ionic strength, membrane voltage and ligand binding.However, the precise mechanisms underlying such diverse modes of activation remain largely unknown.It is found that temperature and capsaicin activate TRPV1 through separate pathways.Here we investigate how extracellular cation activates the heat-sensitive TRPV1 channel.At room temperature, Mg++ ions effectively and selectively activate TRPV 1 from the extracellular side in a dose-dependent manner.The relative open probability induced by 100 mM [Mg++]out is approximately 40% of that elicited by saturating capsaicin, while the same concentration of [Mg++]in is ineffective.Mg++ substantially shifts the temperature sensitivity of the channel.At 10 mM, Mg++ shifts the takeoff temperature of TRPV1 greatly, which implies that the effects of heat and Mg++ are coupled tightly.Furthermore, mutant channels with an artificial pore turret, which have less temperature sensitivity but maintain normal capsaicin responses, also show reduced cation responses.In summary, our observations suggest that in TRPV1 the pore turret may detect both heat and ion strength, and effectively transfer the energy to open the activation gate.